Epstein-Barr virus (EBV) can unleash a fatal immune system overreaction. Short RNA molecules released by the virus cue this response, Iwakiri et al. suggest.
Few people are even aware that they've contracted EBV, as most infections are asymptomatic. But in some cases, the virus can trigger illnesses such as infectious mononucleosis and the potentially lethal EBV-associated hemophagocytic lymphohistiocytosis, in which macrophages destroy large numbers of blood cells. Researchers think that the more severe symptoms of infection result from a tsunami of inflammatory cytokines, but what unleashes this flood wasn't certain.
Iwakiri et al. discovered that the possible culprits are RNA snippets manufactured by the virus. EBV releases two noncoding RNA segments, EBER1 and EBER2, that fold over on themselves to produce double-stranded structures. Using transformed B cells, the researchers showed that EBER1 activates immune cells by prodding Toll-like receptor 3 (TLR3), a sensor of viral double-stranded RNA. Infected cells don't spew out EBER1 when they are dying. Rather, they released the RNA bound to a cellular protein called La, which may help to protect the RNA against degradation.
Blood from patients with mononucleosis and other chronic EBV infections teemed with EBER1, consistent with prior reports. When purified, these viral strands spurred the release of inflammation-promoting cytokines such as interferon-γ and TNF from peripheral blood mononuclear cells.
TLR3 is mainly a dendritic cell (DC) receptor. Indeed, EBER1 induced the maturation of these cells and boosted their ability to present antigens to T cells. The researchers suspect that viral RNA triggers TLR3 on DCs, prompting them to pump out inflammatory cytokines. DCs then enlist T cells that add more cytokines to the mix. In some cases, the result could be a damaging, systematic cytokine surge.
Still a mystery is how releasing RNA benefits EBV. Other viruses use double-stranded RNA to promote infection. Such molecules help the West Nile virus enter the brain, for instance. Iwakiri et al. speculate that RNA might help EBV increase its numbers by promoting division of the cells it infects, including B, T, and natural killer cells.